Translational Control of Splicing Factors Directs Hematopoietic Stem Cell Fate [scRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE295107 | GEO | 2026/06/30
REPOSITORIES: GEO
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Project description:The transition of hematopoietic stem cells (HSCs) from quiescence to differentiation is essential for homeostasis. While transcriptomic control of this process has been extensively studied, the diversity of mRNA isoforms during exit from quiescence remains unexplored. Here, we identify a translationally regulated splicing program governing hematopoietic fate decisions. Splicing factors involved in branch point recognition show dynamic protein-level regulation during HSC differentiation. Among them, Sf1 is translationally controlled via a conserved, structured 5′ UTR. Disrupting translation regulation of Sf1 skews differentiation toward stem cell and erythroid programs. Sf1-dependent alternative splicing affects 5′ UTRs of hematopoietic and DNA damage response genes, altering their translation and impairing DNA damage resolution. These findings reveal an unrecognized link between translational control of spliceosome components, alternative splicing, and HSC fate decisions.
2026-06-30 | GSE294393 | GEO
Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.
2017-09-13 | PXD006054 | Pride
Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Here, we show that dual deficiency for hematopoietic RXRa and RXRb induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRa and RXRb maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRa;RXRb-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRa;RXRb-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.
2022-11-11 | GSE191162 | GEO
Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Here, we show that dual deficiency for hematopoietic RXRa and RXRb induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRa and RXRb maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRa;RXRb-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRa;RXRb-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.
2022-11-11 | GSE191161 | GEO
Project description:Stem cells need to balance self-renewal and differentiation for correct tissue development and homeostasis. Defects in this balance can lead to developmental defects or tumor formation. In recent years, mRNA splicing has emerged as one important mechanism regulating cell fate decisions. Here we address the role of the evolutionary conserved splicing co-factor Barricade (Barc)/CUS2/Tat-SF1 in Drosophila neural stem cell (neuroblast) lineage formation. We show that Barc is required for the generation of neurons during Drosophila brain development by ensuring correct neural progenitor proliferation and differentiation. Barc associates with components of the U2 small nuclear ribonucleic proteins (snRNP), and its depletion causes alternative splicing in form of intron retention in a subset of genes. Using bioinformatics analysis and a cell culture based splicing assay, we found that Barc dependent introns share three major traits: they are short, GC rich and have weak 3’ splice sites. Our results show that Barc, together with the U2snRNP, plays an important role in regulating neural stem cell lineage progression during brain development and facilitates correct splicing of a subset of introns.
2017-11-02 | PXD006068 | Pride
Project description:Alternative splicing is highly prevalent in the brain, orchestrating key processes like neurogenesis and synaptogenesis, which are critical for generating the nervous system's complexity and plasticity. Dysregulation of splicing mechanisms has been increasingly implicated in neurodevelopmental disorders. Splicing factor 1 (SF1) is integral to pre-mRNA processing, facilitating early spliceosome assembly at the 3′ splice site and contributing to the regulation of alternative splicing. Here, we report a newly identified neurodevelopmental disorder associated with de novo heterozygous variants in SF1, characterized by intellectual disability, dysmorphic features, and structural brain anomalies in 15 affected individuals. Functional studies in neural progenitor cells demonstrate that SF1 inhibition alters alternative splicing programs, with pronounced effects on genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. These findings establish SF1-related dysfunction as a novel spliceosomopathy and highlight its critical importance in neurodevelopment and human disease.
2025-07-29 | GSE288121 | GEO
Project description:Hamey2017 - Blood stem cell regulatory
network
This model is described in the article:
Reconstructing blood stem
cell regulatory network models from single-cell molecular
profiles
Fiona K. Hamey, Sonia Nestorowa,
Sarah J. Kinston, David G. Kent, Nicola K. Wilson, and Berthold
Göttgens
Proceedings of the National Academy of
Sciences of the United States of America
Abstract:
Adult blood contains a mixture of mature cell types, each
with specialized functions. Single hematopoietic stem cells
(HSCs) have been functionally shown to generate all mature cell
types for the lifetime of the organism. Differentiation of HSCs
toward alternative lineages must be balanced at the population
level by the fate decisions made by individual cells.
Transcription factors play a key role in regulating these
decisions and operate within organized regulatory programs that
can be modeled as transcriptional regulatory networks. As
dysregulation of single HSC fate decisions is linked to fatal
malignancies such as leukemia, it is important to understand
how these decisions are controlled on a cell-by-cell basis.
Here we developed and applied a network inference method,
exploiting the ability to infer dynamic information from
single-cell snapshot expression data based on expression
profiles of 48 genes in 2,167 blood stem and progenitor cells.
This approach allowed us to infer transcriptional regulatory
network models that recapitulated differentiation of HSCs into
progenitor cell types, focusing on trajectories toward
megakaryocyte–erythrocyte progenitors and lymphoid-primed
multipotent progenitors. By comparing these two models, we
identified and subsequently experimentally validated a
difference in the regulation of nuclear factor, erythroid 2
(Nfe2) and core-binding factor, runt domain, alpha subunit 2,
translocated to, 3 homolog (Cbfa2t3h) by the transcription
factor Gata2. Our approach confirms known aspects of
hematopoiesis, provides hypotheses about regulation of HSC
differentiation, and is widely applicable to other hierarchical
biological systems to uncover regulatory relationships.
This model is hosted on
BioModels Database
and identified by:
MODEL1610060000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-06-09 | MODEL1610060000 | BioModels
Project description:Hamey2017 - Blood stem cell regulatory
network (LMPP network)
This model is described in the article:
Reconstructing blood stem
cell regulatory network models from single-cell molecular
profiles
Fiona K. Hamey, Sonia Nestorowa,
Sarah J. Kinston, David G. Kent, Nicola K. Wilson, and Berthold
Göttgens
Proceedings of the National Academy of
Sciences of the United States of America
Abstract:
Adult blood contains a mixture of mature cell types, each
with specialized functions. Single hematopoietic stem cells
(HSCs) have been functionally shown to generate all mature cell
types for the lifetime of the organism. Differentiation of HSCs
toward alternative lineages must be balanced at the population
level by the fate decisions made by individual cells.
Transcription factors play a key role in regulating these
decisions and operate within organized regulatory programs that
can be modeled as transcriptional regulatory networks. As
dysregulation of single HSC fate decisions is linked to fatal
malignancies such as leukemia, it is important to understand
how these decisions are controlled on a cell-by-cell basis.
Here we developed and applied a network inference method,
exploiting the ability to infer dynamic information from
single-cell snapshot expression data based on expression
profiles of 48 genes in 2,167 blood stem and progenitor cells.
This approach allowed us to infer transcriptional regulatory
network models that recapitulated differentiation of HSCs into
progenitor cell types, focusing on trajectories toward
megakaryocyte–erythrocyte progenitors and lymphoid-primed
multipotent progenitors. By comparing these two models, we
identified and subsequently experimentally validated a
difference in the regulation of nuclear factor, erythroid 2
(Nfe2) and core-binding factor, runt domain, alpha subunit 2,
translocated to, 3 homolog (Cbfa2t3h) by the transcription
factor Gata2. Our approach confirms known aspects of
hematopoiesis, provides hypotheses about regulation of HSC
differentiation, and is widely applicable to other hierarchical
biological systems to uncover regulatory relationships.
This model is hosted on
BioModels Database
and identified by:
MODEL1610060001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-06-09 | MODEL1610060001 | BioModels
Project description:The global gene expression profiles of human umbilical cord blood and adult bone marrow CD34+CD33-CD38-Rho(lo)c-kit+ cells, enriched for hematopoietic stem/progenitor cells (HSC) with CD34+CD33-CD38-Rho(hi) cells, enriched in committed hematopoietic progenitor cells (HPC), were compared to identify candidate regulators of HSC self-renewal versus differentiation fate decisions.
2007-10-30 | E-GEOD-2666 | biostudies-arrayexpress
Project description:Activation of mostly quiescent hematopoietic stem cells (HSC) is a prerequisite for life-long blood production1, 2. This process requires major molecular adaptations to meet the regulatory and metabolic requirements for cell division3-8. The mechanisms governing cellular reprograming upon stem cell activation and their subsequent return to quiescence are still not fully characterized. Here, we describe a role for chaperone-mediated autophagy (CMA)9, a selective form of lysosomal protein degradation, in sustaining adult HSC function. CMA is required for stem cell protein quality control and upregulation of fatty acid metabolism upon HSC activation. We identify that CMA activity decreases with age in HSC and show that genetic or pharmacological activation of CMA can restore functionality of old HSC. Together, our findings provide mechanistic insights into a new role for CMA in sustaining quality control, appropriate energetics and overall long-term hematopoietic stem cell function. Our work supports that CMA may be a promising therapeutic target to enhance hematopoietic stem cell function in conditions such as aging or stem cell transplantation.
2021-03-05 | PXD022196 | Pride